The present invention relates to an improved stannous fluoride composition for the treatment of epidermal irritations and infections.
Stannous fluoride has been used in dentistry since the 1950""s to prevent dental cavities. Norman Tinanoff outlines 40 years of human and animal studies with some studies having greater efficacy than others in xe2x80x9cReview of the Antimicrobial Action of Stannous Fluoridexe2x80x9d (The Journal of Clinical Dentistry Vol. II 1990). U.S. Pat. No. 4,097,590 xe2x80x9cMethods and Compositions for Treatment of Bacteria and Fungus infections of the skinxe2x80x9d discloses treatment for vulgaris and athletes foot with a soluble fluoride salt. The present inventor previously determined that stannous fluoride can be used for treating diseases having viral etiology. (U.S. Pat. No. 5,098,716 to Embro).
Both the shelf life and antimicrobial effect of a stannous fluoride product depend on stability of the active stannous ion (Sn+2). Products formulated for home use achieve stability of the stannous ion by adding glycerin or other water-insoluble materials to reduce hydrolysis and oxidation. Aqueous formulations employed chelating agents which bind stannous fluoride and create a stannous reservoir that acts both as a supply of stannous ions and an antioxidant. Majeti et. al. (U.S. Pat. No. 5,004,597), developed a dentifrice stabilization system for stannous fluoride by utilizing stannous chloride as an antioxidant with stannous reservoir and sodium gluconate as a chelating agent to protect stannous fluoride from hydrolysis. Other chemicals used in stannous fluoride stabilization include polyvinyl alcohol (PVA), tripolyphosphates, copolymers of vinyl-methylether and maleic anhydride. However, the use of these and other complexing agents for stannous fluoride stabilization can limit the bioavailability of stannous ions for a therapeutic effect.
In view of the foregoing, there is a need to provide improved stannous fluoride compositions.
The present invention relates to an improved stannous fluoride composition comprising stannous fluoride and at least one zinc containing compound. The inventor has shown that the improved composition is more stable and less toxic than a stannous fluoride composition that does not contain a zinc compound. The inventor has also shown that the improved composition of the invention allows one to decrease the dose of stannous fluoride required to achieve a therapeutic effect.
The inventor has demonstrated that the improved composition of the invention is effective in treating epidermal irritations and infections and their symptoms. Accordingly, the present invention also provides a method of treating an epidermal irritation or infection comprising administering an effective amount of a composition comprising stannous fluoride and at least one zinc containing compound to an animal in need thereof.
Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
The present invention relates to an improved stannous fluoride composition comprising stannous fluoride and at least one zinc containing compound. This composition may be referred to herein as xe2x80x9cthe composition of the inventionxe2x80x9d.
The composition of the invention is markedly improved over a composition containing stannous fluoride without any zinc compounds in several respects. Firstly, stannous fluoride undergoes hydrolysis and oxidation in aqueous environments which results in the loss of stannous bioavailability due to the precipitation of stannous hydroxide. The zinc containing compounds stabilize the stannous fluoride by preventing the oxidation and hydrolysis of the stannous ion. Zinc ions have a greater affinity than stannous ions for hydroxides and other anions in aqueous solutions. As a result the zinc in the composition of the invention will complex the hydroxides and inhibit hydrolysis and precipitation of the stannous ions. In particular, the inventor has demonstrated that a stannous fluoride solution containing zinc gluconate remained stable, without precipitation, for at least 3 months. In contrast, a stannous fluoride solution without zinc gluconate extensively precipitated. Secondly, the zinc compounds buffer the hydrogen ion which promotes an elevated pH. This makes the composition more suitable for topical use as more acidic formulations can irritate or cause a burning sensation of the skin. Thirdly, the present inventor has unexpectedly found that the zinc compounds act synergistically with and potentiate the activity of the stannous fluoride. In particular, the present inventor has demonstrated that in the composition of the invention the stannous fluoride works better than when twice the dose is used in a composition that does not contain the zinc compounds. Consequently, the dose of the stannous fluoride can be significantly lowered in the composition of the invention resulting in a less toxic composition.
As mentioned above, inclusion of zinc compounds in the composition of the present invention stabilizes and enhances the efficacy of the stannous fluoride. Using zinc containing compounds in the composition also has additional advantages in that zinc is widely recognized as having medicinal and healing properties. In particular, 1) zinc is essential for life; 2) zinc is necessary for over 100 enzymes (i.e., alcohol dehydrogenase carboxypeptidase); 3) zinc maintains body levels of Vitamin A; 4) zinc is important in sex organ function and reproduction; 5) zinc is important for DNA/RNA synthesis; 6) zinc can improve cell-mediated immunity; and 7) zinc is incorporated in hundreds of dermatological formulas to help maintain healthy skin cells. Using stannous compounds with the stannous fluoride will not provide the added benefits that zinc does as stannous is not essential for life and is not necessary for enzyme function.
The zinc containing compound can be any compound containing zinc including zinc carboxylates and zinc salts. The zinc carboxylate is preferably selected from one or more of zinc gluconate, zinc tartrate, zinc malate, zinc propionate, zinc citrate and zinc acetate. More preferably, the zinc carboxylate is zinc gluconate. The zinc salt is preferably selected from zinc chloride, zinc sulfate, zinc phosphate, zinc pyrophosphate, zinc oxide or zinc thiocynate. Preferably, the zinc salt is zinc chloride.
The composition of the invention preferably comprises stannous fluoride in a concentration ranging from about 0.01 wt % to about 10.0 wt % and one or more zinc containing compound in an amount from about 0.05 wt % to about 20.0 wt %.
In a preferred embodiment, the composition comprises stannous fluoride and zinc gluconate. The inventor has shown that a composition comprising stannous fluoride and zinc gluconate provides significantly greater efficacy in the treatment of a viral, bacterial and fungal infections as compared to a stannous fluoride composition alone. In particular, the inventor has demonstrated that with the improved composition one can use one half the amount of stannous fluoride as is used in a composition containing stannous fluoride alone with improved results.
Preferably, the stannous fluoride is provided in a concentration ranging from about 0.1 wt. % to about 8.0 wt. % and zinc gluconate is provided in concentration ranging from about 0.5 wt. % to about 10.0 wt. %. Most preferably, the composition comprises 0.20 % stannous fluoride and 1.5% zinc gluconate, in a non-aqueous medium such as glycerin.
The composition may additionally contain zinc chloride in a concentration ranging from about 0.5 wt. % to about 5.0 wt. %. The addition of zinc chloride may be useful in compositions with a high aqueous content (i.e.  greater than 80% water).
The composition of the invention can include more than one zinc containing compound. For example, the zinc compound may be zinc gluconate, zinc chloride and/or zinc acetate.
The composition may additionally include one of the essential or non-essential xcex1, L or D amino acids selected from the group consisting of lysine, arginine, histidine, phenylalanine, threonine, leucine, isoluceine, cysteine, methionine, valine, alanine, glycine, proline, glutamine, serine, tryptophan, tyrosine and asparagine.
The composition can be formulated using techniques known in the art for example as described in Remington""s Pharmaceutical Sciences, Eighteenth Edition, Mack Publishing Company. The composition is preferably a gel, ointment, cream, lotion, spray or the like, suitable for topical administration. Advantageously, the composition of the present invention maintains its bioavailability at a pH suitable for topical administration. The composition may also include pharmaceutically acceptable diluents or carriers including water, carbopol, glycerin and hydroxymethyl cellulose.
The composition of the invention may additionally include excipients known in the art including fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. In some cases, it may be desirable to add disintegrating agents such as the above mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, steric acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
The compositions of the invention may contain, as additives, preservatives such as p-hydrobenzoates (nipa esters, methylparaben), sorbic acid, chlorhexidine digluconate, benzalkonium chloride and hexadecyltrimethyl ammonium bromide.
In order to accelerate the absorption of the composition through the skin, permeation accelerators such as dimethylsulfoxide or ttauroglycolic acid may be added to the composition.
Hydrogel forming agents which may be used include gelatine and cellulose derivatives such as methyulcellulose, hydroxypropylcellulose and hydroxyethylcellose, as well as synthetic polymers such as polyvinyl alcohol. The nature and quantity of the hydrogel forming agents used or the mixtures thereof will depend on the particular viscosity required.
The additives which may be present also include moisture-retaining substances such as glycerol, sorbitol, 1,2-propyleneglycol, butyleneglycol and polyols.
The inventor has demonstrated that the improved composition of the invention is effective in treating epidermal irritations and infections and their symptoms. Accordingly, the present invention also provides a method of treating an epidermal irritation or infection comprising administering an effective amount of a composition comprising stannous fluoride and at least one zinc containing compound to an animal in need thereof. The zinc containing compound is preferably zinc gluconate and may optionally include zinc chloride.
The term xe2x80x9ceffective amountxe2x80x9d means providing an amount at dosages and for periods of time that is effective to achieve the desired result. The frequency of application of the composition of the invention may range anywhere from one to six times a day, or as needed for the healing process. The course of the therapy typically ranges from one to six times a day, for several days, and may be continued as long as required for complete relief.
The term xe2x80x9canimalxe2x80x9d as used herein includes all members of the animal kingdom. Preferably, the animal is a mammal such as a human, horse, dog or cat.
The term xe2x80x9cepidermal irritationxe2x80x9d means any condition that adversely affects or irritates the skin or coat of an animal including, but not limited to, insect bites, fleas, burns, psoriasis, dermatitis, acne and epidermal infections such as subcutaneous mycoses (sporotrichosis, phycomycosis, phacohypomycosis); Cutaneous Habronemiasis; Cutaneous Onchocerciasis (Onchocerca cervicalis); Seborrhea; Dermatophilosis (Dermatophilus congolensis); Dermatophytosis (Trichophyton equinum, Trichophyton mentagrophytes, Trichophyton verrucosum); Warble fly larvae (Hypoderma spp); or Bot fly larvae (Gasterophilus nasalis/Gasterophilus hemorradalis).
The term xe2x80x9cinfectionxe2x80x9d means any infection including, but not limited to, viral, bacterial, fungal and parasitic infections, that affects animals.
The viral infections that may be treated using the composition of the invention include herpes viruses such as Herpes Simplex I which causes cold sores and Herpes Zoster which causes shingles; Epstein-Barr virus; Papilloma virus which causes warts; cytomegalovirus; hepatitis virus; varicella-zoster virus which causes chicken pox; cold and flu viruses; human and feline leukemia viruses; human immunodeficiency viruses (HIVs) and viruses that cause ringworm.
The bacterial infections that may be treated using the composition of the invention include Streptococcus, Staphlococcus and Dermatophilus skin infections as well as mycoplasmas related to chronic sinus infections.
The fungal infections that may be treated using the composition of the invention include yeast infections of the oral cavity and vagina; fungal infections of the fingernails and feed (athletes foot); and fungal infections of the horse and cow epidermis including infections caused by the genera Microsporum and Trichophyton.
The composition of the invention is particularly well suited for the treatment of epidermal infections such as infections of the skin as well as ocular or eye infections. The inventor has shown that the composition is effective in treating many infections in human patients as well as in other mammals including horses, cats and dogs.
The present invention also provides a use of a composition comprising stannous fluoride and at least one zinc containing compound to treat an epidermal irritation or infection. The invention further provides a use of a composition comprising stannous fluoride and at least one zinc containing compound to prepare a medicament to treat an epidermal irritation or infection.
The following non-limiting examples are illustrative of the present invention: